September 10, 2009
Molecule of the month is an initiative of the RCSB PDB (A Resource for Studying Biological Macromolecules – Protein Data Bank) a protein structure bank. Every month, David Goodsell chooses an interesting structure and describes it, besides illustrating it very well. The illustrations are made available in a high resolution image that may be downloaded.
Goodsell does not limit to give aesthetic appeal to the images, he can also make them become easy to understand sources of information. Follow these two Influenza virus proteins so you are able to see what their structure can inform us.
Hemagglutinin (HA) is a protein located at the virus most external layer, the envelope. It recognizes one sugar of our cell membrane, sialic acid, which it is responsible for the virus recognition and binding to our respiratory system cells.
The name comes from its ability to recognize and to bind to cells and to agglutinate Erythrocyte (red blood cells), one of the first tests developed to diagnose the virus. Its numbers are given based on the amino acids variation; more than 15 types of HA are known, and H1, H2 and H3 are the most common for viruses that infect human beings.
It recognizes our sialic acid through the green portion showed on the above figure and binds to it. Thus, the virus is endocyted by the cell, which means, it is involved by the membrane and taken into a vesicle. The cell tries to digest the vesicle content by decreasing the pH inside the vesicle, but this induces a change in the format of hemagglutinin, exposing the region in red that has great affinity with the vesicle membrane and this way the hemagglutinin twists and approximates the membrane to the virus envelope, fusing both of them and releasing the virus from the vesicle.
Neuraminidase (NA) recognizes the same molecule as hemagglutinin, sialic acid of the cell membrane, but it performs its function in an opposite way, its role is to help the virus to leave the invaded cell.
Neuramidase is needed to remove the acid from the cell and to allow the recently synthesized virus to sprout and invade the next cell. Hence, it is also located on the virus envelope and it is the second most common protein, after hemagglutinin. It is also classified according to its variety and 9 of them are known, being N1 and N2 the most frequent in human beings.
Its ability to recognize and cut sialic acid is jeopardized by inhibitors that we use as antiviral drugs, such as the light blue molecule, attacking NA of the H5N1 virus. As it is located on the virus surface, it is one of the most common antibodies targets, shown in blue on the above figure. Its variation caused by mutations in the influenza genetic material allows new variants not to be recognized anymore by the immune system.
The recognition of different kinds of hosts membrane sugars, role on the infected cell input and output, attack of the immune system and of antivirals are some of the characteristics that make hemagglutinin and neuraminidase important, which are essential to understand the flu and will be frequent visitors of this blog.
Wiley, D., & Skehel, J. (1987). The Structure and Function of the Hemagglutinin Membrane Glycoprotein of Influenza Virus Annual Review of Biochemistry, 56 (1), 365-394 DOI: 10.1146/annurev.bi.56.070187.002053
Skehel, J., & Wiley, D. (2000). RECEPTOR BINDING AND MEMBRANE FUSION IN VIRUS ENTRY: The Influenza Hemagglutinin Annual Review of Biochemistry, 69 (1), 531-569 DOI: 10.1146/annurev.biochem.69.1.531
Colman, P., Varghese, J., & Laver, W. (1983). Structure of the catalytic and antigenic sites in influenza virus neuraminidase Nature, 303 (5912), 41-44 DOI: 10.1038/303041a0